Catheter ablation for atrial fibrillation in elderly patients: an updated meta-analysis of comparative studies.

BACKGROUND: Age is a relevant risk factor for the development of atrial fibrillation (AF) and is associated with increased recurrence rates in the setting of rhythm-control. Catheter ablation is increasingly advocated in elderly despite conflicting data regarding its efficacy and safety in this patient cohort. Therefore, we aimed to analyze currently available evidence regarding catheter ablation for AF in patients ≥75 years compared to younger patients. METHODS: We performed a systematic literature search and meta-analysis on efficacy and safety of catheter ablation in patients ≥75 years with AF. Primary efficacy and safety endpoints were: first recurrence of atrial arrhythmia following first-time ablation and occurrence of death, stroke, or any procedure-related complication. Secondary outcomes included procedure and fluoroscopy time. RESULTS: We identified 301 potentially relevant studies of which 39 underwent detailed analysis. A total of 19 studies (MINORS score ≥13) reporting on 108,419 patients (101,844 <75 years, 6,575 ≥75 years) undergoing first-time catheter ablation for AF were included. Risk of arrhythmia recurrence following catheter ablation (39% vs. 32%; RR [95% CI] 1.24 [1.09-1.41]; P=0.001) and occurrence of safety endpoints (10.8% vs. 8.5%; RR [95% CI] 1.64 [1.53-1.76], P<0.00001) were significantly higher in patients ≥ 75 years compared to younger patients. There was no difference concerning procedure (P=0.33) or fluoroscopy time (P=0.91) between younger and elderly patients. CONCLUSION: In patients ≥75 years of age catheter ablation for AF has higher risk of arrhythmia recurrence and is associated with an increased risk of procedure-related complications and safety endpoint occurrence compared to younger patients.

Niche differentiation within bacterial key-taxa in stratified surface waters of the Southern Pacific Gyre.

One of the most hostile marine habitats on Earth is the surface of the South Pacific Gyre (SPG), characterized by high solar radiation, extreme nutrient depletion and low productivity. During the SO-245 "UltraPac" cruise through the center of the ultra-oligotrophic SPG, the marine alphaproteobacterial group AEGEAN169 was detected by fluorescence in situ hybridization at relative abundances up to 6% of the total microbial community in the uppermost water layer, with two distinct populations (Candidatus Nemonibacter and Ca. Indicimonas). The high frequency of dividing cells combined with high transcript levels, suggest that both clades may be highly metabolically active. Comparative metagenomic and metatranscriptomic analyses of AEGEAN169 revealed that they encoded subtle but distinct metabolic adaptions to this extreme environment in comparison to their competitors SAR11, SAR86, SAR116, and Prochlorococcus. Both AEGEAN169 clades had the highest percentage of transporters per predicted proteins (9.5 and 10.6%, respectively). In particular, the high expression of ABC transporters in combination with proteorhodopsins and the catabolic pathways detected, suggest a potential scavenging lifestyle for both AEGEAN169 clades. Although both AEGEAN169 clades may share the genomic potential to utilize phosphonates as a phosphorus source, they differ in their metabolic pathways for carbon and nitrogen. Ca. Nemonibacter potentially use glycine-betaine, whereas Ca. Indicimonas may catabolize urea, creatine, and fucose. In conclusion, the different potential metabolic strategies of both clades suggest that both are well adapted to thrive resource-limited conditions and compete well with other dominant microbial clades in the uppermost layers of SPG surface waters.

Oxygen accumulation and associated dangers in rescue helicopters.

BACKGROUND: At the time of the COVID-19 pandemic, devastating incidents increased due to frequent oxygen administration to patients. The dangers associated with the use of oxygen, especially through local enrichments and formation of "oxygen clouds", have been well understood for years. Nevertheless, dramatic incidents continue to occur, since fire hazard increases exponentially with oxygen concentrations above 23%. Rescue helicopters are at a particular high risk, because of technical reasons such as oxygen use in a very small space, surrounded by kerosene lines, electronic relays and extremely hot surfaces. METHODS: In this study three different sized rescue helicopter models (Airbus H135, H145 and MD902) were examined. Oxygen enrichment in the cabin was measured with an oxymeter during a delivery rate of 15 l/min constant flow for 60 min. Furthermore, the clearance of the enriched atmosphere was tested in different situations and with different ventilation methods. To make the airflow visible, a fog machine was used to fill the helicopter cabin. RESULTS: Oxygen accumulation above 21% was detected in every helicopter. After 10-15 min, the critical 23% threshold was exceeded in all three aircrafts. The highest concentration was detected in the smallest machine (MD902) after 60 min with 27.4%. Moreover, oxygen clouds persisted in the rear and the bottom of the aircrafts, even when the front doors were opened. This was most pronounced in the largest aircraft, the H145 from Airbus Helicopters. Complete and rapid removal of elevated oxygen concentrations was achieved only by cross-ventilation within 1 min. CONCLUSIONS: Oxygen should be handled with particular care in rescue helicopters. Adapted checklists and precautions can help to prevent oxygen accumulation, and thus, fatal incidents. To our knowledge, this is the first study, which analyzed oxygen concentrations in different settings in rescue helicopters.

Angiotensin Receptor-Neprilysin Inhibitor Is Associated With Improved Cardiac Autonomic Function in Heart Failure.

BACKGROUND: Heart failure with reduced ejection fraction is associated with potentially deleterious imbalance of the cardiac autonomic nervous system. Sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNI]) reduces cardiovascular mortality and hospitalization for heart failure with reduced ejection fraction. Whether ARNI affects the cardiac autonomic nervous system has not been studied. METHODS AND RESULTS: This investigator-initiated, prospective, single-center cohort study compared heart rate (HR) variability, HR, deceleration capacity, and periodic repolarization dynamics as noninvasive measures of the cardiac autonomic nervous system before and after initiation of ARNI therapy. Patients underwent standardized 12-lead Holter-ECG, echocardiography and laboratory testing before and 3 months after start of therapy. End points were changes in HR variability (SD of normal-to-normal intervals, mean square of differences between consecutive R-R intervals), HR, deceleration capacity, and periodic repolarization dynamics as well as ventricular function and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Of 63 patients with heart failure with reduced ejection fraction enrolled, 48 (76.2%) patients were still on ARNI at follow-up. SD of normal-to-normal intervals increased from 25 to 36 milliseconds (P<0.001), mean square of differences between consecutive R-R intervals increased from 12 to 19 milliseconds (P<0.001), HR decreased from 73±9 bpm to 67±4 bpm, (P<0.001), and deceleration capacity increased from 2.1 to 4.4 milliseconds (P<0.001). A trend for periodic repolarization dynamics reduction was observed (5.6 deg2 versus 4.7 deg2, P=0.09). Autonomic changes were accompanied by increased left ventricular ejection fraction (29±6% versus 40±8%, P<0.001) and reduced NT-proBNP (3548 versus 685 ng/L, P<0.001). Correlation analysis showed a significant relationship between volume-unloading (as evidenced by NT-proBNP reduction) and autonomic improvement. CONCLUSIONS: Three months of ARNI therapy resulted in a significant increase in cardiac parasympathetic tone. The improvement in autonomic properties may be mediated by "volume unloading" and likely contributes to the beneficial effects of ARNI in heart failure with reduced ejection fraction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04587947.

Pulmonary Vein Isolation or Pace and Ablate in Elderly Patients With Persistent Atrial Fibrillation (ABLATE Versus PACE)-Rationale, Methods, and Design.

Age is a major risk-factor for atrial fibrillation (AF) and associated hospitalisations. With increasing emphasis on rhythm control, pulmonary vein isolation (PVI) is often suggested, even to elderly patients (≥ 75 years of age). Efficacy of PVI aiming at rhythm control is limited in persistent AF. Pacemaker implantation with atrioventricular node (AVN) ablation may represent a reasonable alternative, with the aim of controlling symptoms and improving quality of life in elderly patients. In this investigator-initiated, randomised, multicentre trial, we test the hypothesis that pacemaker implantation and AVN ablation provides superior symptom control over PVI in elderly patients with symptomatic persistent AF, without any increase in adverse event profile. In the ABLATE Versus PACE (NCT04906668) prospective open-label superiority trial, 196 elderly patients with normal ejection fraction and symptomatic persistent AF despite guideline-indicated medical therapy will be randomised to either cryoballoon PVI (ABLATE) or dual-chamber pacemaker implantation with subsequent AVN ablation (PACE), and followed for a minimum of 12 months. The primary efficacy outcome is a composite end point of rehospitalisation for atrial arrhythmia or cardiac decompensation/heart failure, (outpatient) electrical cardioversion, or upgrade to cardiac resynchronisation therapy owing to worsening of left ventricular ejection fraction to ≤ 35%. Secondary end points include death from any cause, stroke, quality of life, and procedure-related complications. Sample size is designed to achieve 80% power for the primary end point (2-tailed alpha of 5%). ABLATE Versus PACE will determine whether pacemaker implantation and AVN ablation can improve symptom-control in elderly patients with persistent AF over PVI without increasing safety end points.

Globally occurring pelagiphage infections create ribosome-deprived cells.

Phages play an essential role in controlling bacterial populations. Those infecting Pelagibacterales (SAR11), the dominant bacteria in surface oceans, have been studied in silico and by cultivation attempts. However, little is known about the quantity of phage-infected cells in the environment. Using fluorescence in situ hybridization techniques, we here show pelagiphage-infected SAR11 cells across multiple global ecosystems and present evidence for tight community control of pelagiphages on the SAR11 hosts in a case study. Up to 19% of SAR11 cells were phage-infected during a phytoplankton bloom, coinciding with a ~90% reduction in SAR11 cell abundance within 5 days. Frequently, a fraction of the infected SAR11 cells were devoid of detectable ribosomes, which appear to be a yet undescribed possible stage during pelagiphage infection. We dubbed such cells zombies and propose, among other possible explanations, a mechanism in which ribosomal RNA is used as a resource for the synthesis of new phage genomes. On a global scale, we detected phage-infected SAR11 and zombie cells in the Atlantic, Pacific, and Southern Oceans. Our findings illuminate the important impact of pelagiphages on SAR11 populations and unveil the presence of ribosome-deprived zombie cells as part of the infection cycle.

Left Ventricular Hypertrophy After Renal Transplantation: Systematic Review and Meta-analysis.

Background: Left ventricular hypertrophy (LVH) in patients with end stage renal disease undergoing renal replacement is linked to an increased risk for cardiovascular diseases. Dialysis does not completely prevent or correct this abnormality, and the evidence for kidney transplantation (KT) varies. This analysis aims to explore the relationship between KT and LVH. Methods: MEDLINE and Scopus were systematically searched in October 2023. All cross-sectional and longitudinal studies that fulfilled our inclusion criteria were included. Outcome was left ventricular mass index (LVMI) changes. We conducted a meta-analysis using a random effects model. Meta-regression was applied to examine the LVMI changes dependent on various covariates. Sensitivity analysis was used to handle outlying or influential studies and address publication bias. Results: From 7416 records, 46 studies met the inclusion criteria with 4122 included participants in total. Longitudinal studies demonstrated an improvement of LVMI after KT -0.44 g/m2 (-0.60 to -0.28). Blood pressure was identified as a predictor of LVMI change. A younger age at the time of KT and well-controlled anemia were also associated with regression of LVH. In studies longitudinally comparing patients on dialysis and renal transplant recipients, no difference was detected -0.09 g/m2 (-0.33 to 0.16). Meta-regression using changes of systolic blood pressure as a covariate showed an association between higher blood pressure and an increase in LVMI, regardless of the modality of renal replacement treatment. Conclusions: In conclusion, our results indicated a potential cardiovascular benefit, defined as the regression of LVH, after KT. This benefit was primarily attributed to improved blood pressure control rather than the transplantation itself.

Characterization of the Coordination and Solvation Dynamics of Solvated Systems─Implications for the Analysis of Molecular Interactions in Solutions and Pure H2O.

The characterization of solvation shells of atoms, ions, and molecules in solution is essential to relate solvation properties to chemical phenomena such as complex formation and reactivity. Different definitions of the first-shell coordination sphere from simulation data can lead to potentially conflicting data on the structural properties and associated ligand exchange dynamics. The definition of a solvation shell is typically based on a given threshold distance determined from the respective solute-solvent pair distribution function g(r) (i.e., GC). Alternatively, a nearest neighbor (NN) assignment based on geometric properties of the coordination complex without the need for a predetermined cutoff criterion, such as the relative angular distance (RAD) or the modified Voronoi (MV) tessellation, can be applied. In this study, the effect of different NN algorithms on the coordination number and ligand exchange dynamics evaluated for a series of monatomic ions in aqueous solution, carbon dioxide in aqueous and dichloromethane solutions, and pure liquid water has been investigated. In the case of the monatomic ions, the RAD approach is superior in achieving a well separated definition of the first solvation layer. In contrast, the MV algorithm provides a better separation of the NNs from a molecular point of view, leading to better results in the case of solvated CO2. When analyzing the coordination environment in pure water, the cutoff-based GC framework was found to be the most reliable approach. By comparison of the number of ligand exchange reactions and the associated mean ligand residence times (MRTs) with the properties of the coordination number autocorrelation functions, it is shown that although the average coordination numbers are sensitive to the different definitions of the first solvation shell, highly consistent estimates for the associated MRT of the solvated system are obtained in the majority of cases.

Nociceptive Flexion Reflex Threshold is No Suitable Marker for Diagnosing Opioid-Induced Hyperalgesia.

Background: Opioid induced hyperalgesia (OIH) describes a state of altered pain sensation due to opioid exposure. It often occurs among persons with opioid use disorder receiving substitution therapy. Methods: The purpose of this study was to find out, whether OIH diagnosis could be facilitated by an objective pain indicating marker: the Nociceptive Flexion Reflex (NFR). Forty persons with opioid use disorder, 20 of them maintained on methadone and 20 treated with buprenorphine, as well as a control group of 20 opioid-free subjects, were examined. It was aimed to find out whether and in which way these opioid agonists alter reflex threshold (NFR-T). A cold-pressor test was performed to investigate the prevalence of OIH. Furthermore, electrical stimulation and electromyography analyzation were used for NFR-T measurement. Subjective pain ratings were evaluated with a numeric rating scale. Results: Significantly increased sensitivity to cold pressor pain was found in both maintenance groups when compared to their opioid-free counterparts (p < 0.001). Neither methadone nor buprenorphine showed any effect on NFR-T. This might be explained by the reflex approaching at the wrong location in the central nervous system. Consequently, NFR-T is not a suitable marker for diagnosing OIH. Conclusion: Although methadone and buprenorphine have been proven to cause OIH, no effect on NFR-T was observed. A statistically significant effect could have been observed with a larger number of participants. Further research, with special focus on patients' adjuvant medication, should be conducted in the future, to facilitate diagnosis of OIH and provide appropriate pain management for maintenance patients.

Prevalence of strabismus and risk factors in adults born preterm with and without retinopathy of prematurity: results from the Gutenberg Prematurity Eye study.

AIM: The purpose of this study was to assess the prevalence of strabismus and nystagmus and to analyse associated factors in preterm and full-term infants in adulthood. METHODS: The Gutenberg Prematurity Eye Study is a retrospective cohort study with a prospective ophthalmological examination of participants born preterm and full-term (aged 18-52 years). Perinatal data were carefully assessed for risk factors and comprehensive ophthalmological examinations were conducted. The association between strabismus and nystagmus was assessed by analysing 16 different perinatal and actual risk factors in multivariable analysis. Participants were grouped into full-term controls (gestational age (GA) at birth ≥37 weeks), preterm participants without retinopathy of prematurity (ROP) and GA 33-36 weeks (group 2), GA 29-32 weeks (group 3), GA ≤28 weeks (group 4), non-treated ROP (group 5) and treated ROP (group 6). RESULTS: In total, 892 eyes of 450 preterm and full-term individuals (mean age: 28.6 years, SD: ± 8.6 years, 251 females) were included. Strabismus was observed in 2.1% (3/140), 6.6% (9/137), 17.4% (16/92), 11.1% (2/18), 27.1% (13/48) and 60% (9/15) of participants and nystagmus in 0.7% (1/140), 1.5% (2/137), 4.3% (4/92), 5.6% (1/18), 10.4% (5/48) and 26.7% (4/15) of participants in the respective groups. In the multivariable regression model, strabismus was associated with GA (OR=0.90; p=0.046), anisometropia ≥1.5 diopter (OR=3.87; p=0.003), hypermetropia ≥2 diopter (OR=9.89; p<0.001) and astigmatism ≥1.5 diopter (OR=2.73; p=0.017). Esotropia was more frequent than exotropia and hypermetropia/hypometropia. Most strabismus cases occurred within the first 10 years of life. The strongest predictor associated with nystagmus was perinatal adverse events (OR=15.8; p=0.002). CONCLUSION: Low GA and refraction of the eye are independent risk factors for strabismus, which typically occurs in the first 10 years of life. Perinatal adverse events are the most important factors for the presence of nystagmus in adulthood.

Particle-attached bacteria act as gatekeepers in the decomposition of complex phytoplankton polysaccharides.

BACKGROUND: Marine microalgae (phytoplankton) mediate almost half of the worldwide photosynthetic carbon dioxide fixation and therefore play a pivotal role in global carbon cycling, most prominently during massive phytoplankton blooms. Phytoplankton biomass consists of considerable proportions of polysaccharides, substantial parts of which are rapidly remineralized by heterotrophic bacteria. We analyzed the diversity, activity, and functional potential of such polysaccharide-degrading bacteria in different size fractions during a diverse spring phytoplankton bloom at Helgoland Roads (southern North Sea) at high temporal resolution using microscopic, physicochemical, biodiversity, metagenome, and metaproteome analyses. RESULTS: Prominent active 0.2-3 µm free-living clades comprised Aurantivirga, "Formosa", Cd. Prosiliicoccus, NS4, NS5, Amylibacter, Planktomarina, SAR11 Ia, SAR92, and SAR86, whereas BD1-7, Stappiaceae, Nitrincolaceae, Methylophagaceae, Sulfitobacter, NS9, Polaribacter, Lentimonas, CL500-3, Algibacter, and Glaciecola dominated 3-10 µm and > 10 µm particles. Particle-attached bacteria were more diverse and exhibited more dynamic adaptive shifts over time in terms of taxonomic composition and repertoires of encoded polysaccharide-targeting enzymes. In total, 305 species-level metagenome-assembled genomes were obtained, including 152 particle-attached bacteria, 100 of which were novel for the sampling site with 76 representing new species. Compared to free-living bacteria, they featured on average larger metagenome-assembled genomes with higher proportions of polysaccharide utilization loci. The latter were predicted to target a broader spectrum of polysaccharide substrates, ranging from readily soluble, simple structured storage polysaccharides (e.g., laminarin, α-glucans) to less soluble, complex structural, or secreted polysaccharides (e.g., xylans, cellulose, pectins). In particular, the potential to target poorly soluble or complex polysaccharides was more widespread among abundant and active particle-attached bacteria. CONCLUSIONS: Particle-attached bacteria represented only 1% of all bloom-associated bacteria, yet our data suggest that many abundant active clades played a pivotal gatekeeping role in the solubilization and subsequent degradation of numerous important classes of algal glycans. The high diversity of polysaccharide niches among the most active particle-attached clades therefore is a determining factor for the proportion of algal polysaccharides that can be rapidly remineralized during generally short-lived phytoplankton bloom events. Video Abstract.

Insight into planktonic protistan and fungal communities across the nutrient-depleted environment of the South Pacific Subtropical Gyre.

Ocean microorganisms constitute ~70% of the marine biomass, contribute to ~50% of the Earth's primary production, and play a vital role in global biogeochemical cycles. The marine heterotrophic and mixotrophic protistan and fungal communities have often been overlooked mainly due to limitations in morphological species identification. Despite the accumulation of studies on biogeographic patterns observed in microbial communities, our understanding of the abundance and distribution patterns within the microbial community of the largest subtropical gyre, the South Pacific Gyre (SPG), remains incomplete. Here, we investigated the diversity and vertical composition of protistan and fungal communities in the water column of the ultra-oligotrophic SPG. Our results showed apparent differences in protistan community diversity in the photic and aphotic regions. The entire protistan community diversity was significantly affected by temperature, salinity, oxygen, and nutrient concentrations, while the parasitic community diversity was also affected by chlorophyll a concentration. The parasitic protists were assigned to the class Syndiniales accounting for over 98% of the total parasitic protists, exhibiting higher relative sequence abundance along the water depth and displaying consistent patterns among different sampling stations. In contrast to the protistan community, the fungal community along the SPG primarily clustered based on the sampling station and pelagic zones. In particular, our study reveals a significant presence of parasitic protists and functionally diverse fungi in SPG and their potential impact on carbon cycling in the gyre.IMPORTANCEOur findings carry important implications for understanding the distribution patterns of the previously unrecognized occurrence of parasitic protists and functionally diverse fungi in the nutrient-limited South Pacific Gyre. In particular, our study reveals a significant presence of parasitic Syndiniales, predominantly abundant in the upper 300 m of the aphotic zone in the gyre, and a distinct presence of fungal communities in the aphotic zone at the central part of the gyre. These findings strongly suggest that these communities play a substantial role in yet insufficiently described microbial food web. Moreover, our research enhances our understanding of their contribution to the dynamics of the food webs in oligotrophic gyres and is valuable for projecting the ecological consequences of future climate warming.

Intracerebral haemorrhage in patients taking different types of oral anticoagulants: a pooled individual patient data analysis from two national stroke registries.

BACKGROUND: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation. METHODS: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months. RESULTS: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%)). CONCLUSIONS: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future.

Determination of glomerular filtration rate "en passant" after high doses of iohexol for computed tomography in intensive care medicine-a proof of concept.

Accurate assessment of renal function is of great clinical and scientific importance, as it is an important pharmacokinetic covariate of pivotal drugs. The iohexol clearance is nearly identical to the glomerular filtration rate, but its determination usually requires an intravenous injection and therefore bears intrinsic risks. This motivates to showcase an "en passant" approach to quantification of renal function without additional risk or blood sampling beyond routine care using real-world data. We enrolled 37 intensive care patients who received high doses of iohexol for computed tomography imaging, and quantified series of iohexol plasma concentrations by high-performance liquid chromatography (HPLC-UV). Iohexol clearance was derived by both log-linear regression and nonlinear least squares fitting and compared to glomerular filtration rate estimated by the CKD-EPI-2021 formulas. Nonlinear fitting not only turned out to be more accurate but also more robust in handling the irregularly timed data points. Concordance of iohexol clearance against estimations based on both creatinine and cystatin C showed a slightly higher bias (-3.44 mL/min/1.73 m2) compared to estimations based on creatinine alone (-0.76 mL/min/1.73 m2), but considerably narrower limits of agreement (±42.8 vs. 56 mL/min/1.73 m2) and higher Lin's correlation (0.84 vs. 0.72). In summary, we have demonstrated the feasibility and performance of the "en passant" variant of the iohexol method in intensive care medicine and described a working protocol for its application in clinical practice and pharmacologic studies.

Pulmonary Vein Isolation in Elderly Patients ≥ 75 Years: A Propensity Score-Matched Analysis With Focus on Differences Among Atrial Fibrillation Types.

BACKGROUND: Age is a major risk factor for development of atrial fibrillation (AF) and associated with increased recurrence rates in the setting of rhythm control. Current data tend to support catheter ablation in elderly patients, but uncertainties exist regarding efficacy and safety of ablation in elderly patients. METHODS: This was a prospective single-centre observational study with propensity score matching (PSM) to investigate the influence of age on efficacy and safety of cryoballoon ablation (CBA) stratified by age (< 75 years vs ≥ 75 years) and AF phenotype (paroxysmal vs persistent). Primary efficacy endpoint was recurrence of atrial arrhythmia after a 90-day blanking period. Safety endpoints were death, stroke, or procedure-associated complications. RESULTS: Consecutive patients (n = 953) underwent CBA for first-time AF ablation. Median follow-up was 18 months. By means of PSM, 268 matches were formed. At 1 year, primary efficacy endpoint occurred in 22.4% of young vs 33.2% of elderly patients, including both AF phenotypes (hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.47-0.90; P = 0.01). AF relapse occurred in 19.7% of young vs 28.5% of elderly patients with paroxysmal (HR, 0.63; 95% CI, 0.40-0.99; P = 0.046) compared with 25.9% (30 of 116, young) vs 38.8% (45 of 116, elderly) patients with persistent AF (HR, 0.62; 95% CI, 0.39-0.97; P = 0.038). No difference was observed regarding the incidence of safety endpoints between young and elderly patients (P = 0.38). CONCLUSIONS: CBA is associated with higher recurrence rates in elderly (≥ 75 years) than in younger patients, with highest recurrence rates in elderly patients with persistent AF.

CADMUS: A Novel MRI-Based Classification of Spontaneous Intracerebral Hemorrhage Associated With Cerebral Small Vessel Disease

BACKGROUND AND OBJECTIVES: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH. METHODS: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses. RESULTS: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes. DISCUSSION: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Andexanet alfa versus non-specific treatments for intracerebral hemorrhage in patients taking factor Xa inhibitors - Individual patient data analysis of ANNEXA-4 and TICH-NOAC.

BACKGROUND: Data comparing the specific reversal agent andexanet alfa with non-specific treatments in patients with non-traumatic intracerebral hemorrhage (ICH) associated with factor-Xa inhibitor (FXaI) use are scarce. AIM: The study aimed to determine the association between the use of andexanet alfa compared with non-specific treatments with the rate of hematoma expansion and thromboembolic complications in patients with FXaI-associated ICH. METHODS: We performed an individual patient data analysis combining two independent, prospective studies: ANNEXA-4 (180 patients receiving andexanet alfa, NCT02329327) and TICH-NOAC (63 patients receiving tranexamic acid or placebo ± prothrombin complex concentrate, NCT02866838). The primary efficacy outcome was hematoma expansion on follow-up imaging. The primary safety outcome was any thromboembolic complication (ischemic stroke, myocardial infarction, pulmonary embolism, or deep vein thrombosis) at 30 days. We used binary logistic regression models adjusted for baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively. RESULTS: Among 243 participants included, the median age was 80 (IQR 75-84) years, baseline hematoma volume was 9.1 (IQR 3.4-21) mL and anti-Xa activity 118 (IQR 78-222) ng/mL. Times from last FXaI intake and symptom onset to treatment were 11 (IQR 7-16) and 4.7 (IQR 3.0-7.6) h, respectively. Overall, 50 patients (22%) experienced hematoma expansion (ANNEXA-4: n=24 (14%); TICH-NOAC: n=26 (41%)). After adjusting for pre-specified confounders (baseline hematoma volume, age, calibrated anti-Xa activity, times from last intake of FXaI, and symptom onset to treatment, respectively), treatment with andexanet alfa was independently associated with decreased odds for hematoma expansion (aOR 0.33, 95% CI 0.13-0.80, p = 0.015). Overall, 26 patients (11%) had any thromboembolic complication within 30 days (ANNEXA-4: n=20 (11%); TICH-NOAC: n=6 (10%)). There was no association between any thromboembolic complication and treatment with andexanet alfa (aOR 0.70, 95% CI 0.16-3.12, p = 0.641). CONCLUSION: The use of andexanet alfa compared to any other non-specific treatment strategy was associated with decreased odds for hematoma expansion, without increased odds for thromboembolic complications.

Time for "code ICH"? - Workflow metrics of hyperacute treatments and outcome in patients with intracerebral haemorrhage.

INTRODUCTION: Knowledge about uptake and workflow metrics of hyperacute treatments in patients with non-traumatic intracerebral haemorrhage (ICH) in the emergency department are scarce. METHODS: Single centre retrospective study of consecutive patients with ICH between 01/2018-08/2020. We assessed uptake and workflow metrics of acute therapies overall and according to referral mode (stroke code, transfer from other hospital or other). RESULTS: We enrolled 332 patients (age 73years, IQR 63-81 and GCS 14 points, IQR 11-15, onset-to-admission-time 284 minutes, IQR 111-708minutes) of whom 101 patients (35%) had lobar haematoma. Mode of referral was stroke code in 129 patients (38%), transfer from other hospital in 143 patients (43%) and arrival by other means in 60 patients (18%). Overall, 143 of 216 (66%) patients with systolic blood pressure >150mmHG received IV antihypertensive and 67 of 76 (88%) on therapeutic oral anticoagulation received prothrombin complex concentrate treatment (PCC). Forty-six patients (14%) received any neurosurgical intervention within 3 hours of admission. Median treatment times from admission to first IV-antihypertensive treatment was 38 minutes (IQR 18-72minutes) and 59 minutes (IQR 37-111 minutes) for PCC, with significant differences according to mode of referral (p<0.001) but not early arrival (≤6hours of onset, p=0.92). The median time in the emergency department was 139 minutes (IQR 85-220 minutes) and among patients with elevated blood pressure, only 44% achieved a successful control (<140mmHG) during ED stay. In multivariate analysis, code ICH concordant treatment was associated with significantly lower odds for in-hopsital mortality (aOR 0.30, 95%CI 0.12-0.73, p=0.008) and a non-significant trends towards better functional outcome measured using the modified Rankin scale score at 3 months (aOR for ordinal shift 0.54 95%CI 0.26-1.12, p=0.097). CONCLUSION: Uptake of hyperacute therapies for ICH treatment in the ED is heterogeneous. Treatment delays are short but not all patients achieve treatment targets during ED stay. Code ICH concordant treatment may improve clinical outcomes. Further improvements seem achievable advocating for a "code ICH" to streamline acute treatments.

Array-Based Comparative Genomic Hybridization for the Detection of Copy Number Alterations in Single Cells.

Comprehensive genome-wide analyses of single cells represent an important tool for clinical applications, such as pre-implantation diagnostic and prenatal diagnosis, as well as for cancer research purpose. For the latter, studies of tumor heterogeneity, circulating tumor cells (CTCs), and disseminated cancer cells (DCCs) require the analysis of single-cell genomes. Here we describe a reliable and robust array-based comparative genomic hybridization (aCGH) protocol based on Ampli 1™ whole genome amplification that allows the detection of copy number alterations (CNAs) in single cancer cells as small as 100 kb.

Isolation and Genomic Analysis of Circulating Tumor Cell Clusters in Cancer Patients.

The role of circulating tumor cell (CTC) clusters in the metastatic dissemination process is gaining increased attention. Besides homotypic clusters, heterotypic clusters that contain tumor cells admixed with normal cells are frequently observed in patients with solid tumors. Current methods used for cluster detection and enumeration do not allow an accurate estimation of the relative fractions of tumor cells. Here we describe a method for estimating tumor fraction of clusters including isolation and collection of single clusters, assessment of copy number alterations of single clusters by low-pass whole genome sequencing, and bioinformatic analysis of sequencing data.